title: Synergistic activity of 5-substituted 2-nitroimidazoles (Ro 15-0216 and benznidazole) and DL-alpha-difluoromethylornithine on Trypanosoma brucei brucei.
abstract: The antitrypanosomal activity of two 5-substituted 2-nitro-imidazoles (Ro 15-0216 and benznidazole) and alpha-DL-difluoro-methylornithine (DFMO) was tested in four stocks of Trypanosoma brucei brucei in vitro. The IC50 (drug concentration which inhibits growth of trypanosome populations by 50%) values ranged from 0.27-1.0 for Ro 15-0216, 84-265 for benznidazole, and 147-691 microM for DFMO. Potentiation of antitrypanosomal activity of the combination of Ro 15-0216 and DFMO was demonstrated in a 24 h growth inhibition test. A synergistic effect was also demonstrated when benznidazole and DFMO were combined in a long term viability assay in vitro. Although 40 microM DFMO and 20 microM benznidazole were ineffective when used individually, trypanosomes of all stocks were killed when both drugs were present simultaneously at these concentrations. The combination of 40 microM DFMO and 4 microM benznidazole led to growth suppression. At an early stage of infection, a single injection of 100 mg/kg Ro 15-0216 at the end of a 3-day treatment period with DFMO (2% in drinking water) resulted in a 100% cure of T. b. brucei-infected mice, whereas monotherapy with either drug at the same dose levels was completely ineffective. Nitroimidazoles and DFMO given simultaneously might improve the therapy of human sleeping sickness.
authors.affiliation: Kenya Trypanosomiasis Research Institute, Kikuyu.
authors.forename: E
authors.initials: E
authors.lastname: Zweygarth
authors.forename: R
authors.initials: R
authors.lastname: Kaminsky
authors.forename: P D
authors.initials: PD
authors.lastname: Sayer
authors.forename: S
authors.initials: S
authors.lastname: van Nieuwenhove
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D000518:Eflornithine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009593:Nitroimidazoles / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000083:Acetanilides; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C054646:Ro 15-0216; C009999:benzonidazole; D000518:Eflornithine